SRC proteins can link receptor tyrosine kinases to critical downstream oncogenic pathways such as PI3K/PTEN/Akt, STATs, and Ras/Raf/ERK. Regulation of these key pathways allows SRC to control cellular growth and proliferation, survival, invasion, and angiogenesis. Based on the importance of EGFR signaling in lung cancer and the known cooperation between EGFR and SRC proteins, we evaluated the effectiveness of novel SRC inhibitors in lung cancer cell lines with defined EGFR status. SRC inhibition reduces mutant EGFR lung cancer cell viability through the induction of apoptosis while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of activated Akt and StatS survival proteins. In cell lines without EGFR mutation, SRC inhibition reduces cyclin D and increases p27 protein levels with a corresponding G1 cell cycle arrest. SRC inhibition also inhibits activated FAK and inhibits lung cancer cell invasion. These data demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers, especially those driven by mutant EGFR proteins. The goal of this research proposal is to further characterize the effect of novel SRC kinase inhibitors in lung cancer cells. In specific aim 1, we will characterize the effect of SRC inhibitors on apoptosis and growth inhibition in lung cancer cells with defined EGFR status. We will evaluate the effects on key downstream pathways that control apoptosis and cell growth such as PI3K/PTEN/Akt and STATs. We will evaluate the effect of combined EGFR and SRC tyrosine kinase inhibitors on apoptosis and growth inhibition. In specific aim 2, we will evaluate the effect of SRC inhibition on tumor growth in vivo in lung cancer xenograft models with corresponding biomarker analysis. We plan to test the hypothesis that SRC inhibitor treatment of lung cancer xenografts with EGFR mutation will undergo tumor regression through enhanced apoptosis while treatment of xenografts with wildtype EGFR will result in growth inhibition. Biomarkers of response defined in the above aim will be further validated in these models. In specific aim 3, two investigator-initiated patient-based clinical trial trials are proposed: (i) a phase I trial of erlotinib and dasatinib in previously treated NSCLC and (ii) a phase II trial of dasatinib in previously treated NSCLC along with biomolecular analysis based on our preliminary data and mechanisms defined in Aims 1&2. [unreadable] [unreadable] [unreadable]